








key: cord-289304-9srk0ohb
authors: Bagnato, Sergio; Boccagni, Cristina; Marino, Giorgio; Prestandrea, Caterina; D’Agostino, Tiziana; Rubino, Francesca
title: Critical illness myopathy after COVID-19
date: 2020-08-05
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.07.072
sha: 
doc_id: 289304
cord_uid: 9srk0ohb

We describe a patient who developed diffuse and symmetrical muscle weakness after a long stay in the intensive care unit (ICU) due to coronavirus disease 2019 (COVID-19). The patient underwent a neurophysiological protocol, including nerve conduction studies, concentric needle electromyography (EMG) of the proximal and distal muscles, and direct muscle stimulation (DMS). Nerve conduction studies showed normal sensory conduction and low-amplitude compound muscle action potentials (CMAPs). EMG revealed signs of myopathy, which were more pronounced in the lower limbs. The post-DMS CMAP was absent in the quadriceps and of reduced amplitude in the tibialis anterior muscle. Based on these clinical and neurophysiological findings, a diagnosis of critical illness myopathy was made according to the current diagnostic criteria. Given the large number of patients with COVID-19 who require long ICU stays, many of these patients are very likely to develop ICU-acquired weakness, as did the patient described here. Health systems must plan to provide adequate access to rehabilitative facilities for both pulmonary and motor rehabilitative treatment after COVID-19.

We describe a patient who developed diffuse and symmetrical muscle weakness after a long stay in the intensive care unit (ICU) due to coronavirus disease 2019 . The patient underwent a neurophysiological protocol, including nerve conduction studies, concentric needle electromyography (EMG) of the proximal and distal muscles, and direct muscle stimulation (DMS).

Nerve conduction studies showed normal sensory conduction and low-amplitude compound muscle action potentials (CMAPs). EMG revealed signs of myopathy, which were more pronounced in the lower limbs. The post-DMS CMAP was absent in the quadriceps and of reduced amplitude in the tibialis anterior muscle. Based on these clinical and neurophysiological findings, a diagnosis of critical illness myopathy was made according to the current diagnostic criteria. Given the large number of patients with COVID-19 who require long ICU stays, many of these patients are very likely to develop ICU-acquired weakness, as did the patient described here. Health systems must plan to provide adequate access to rehabilitative facilities for both pulmonary and motor rehabilitative

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which reached pandemic-level diffusion in March 2020. Patients with COVID-19 frequently experience muscular symptoms, such as myalgia, but myopathic changes have not been evaluated fully in this population. A recent review of the neurological complications of included 25 studies with data on skeletal muscle problems, but no study examining the use of electromyography or another diagnostic test to detect myopathic changes (Pinzon et al., 2020) .

Notably, an unexpectedly large number of patients with COVID-19 requires intensive care unit (ICU) admission and long stays (Lewnard et al., 2020) . Critically ill patients are likely to develop muscular complications, such as critical illness myopathy (CIM), which adversely affect short-and long-term outcomes (Vanhorebeek et al., 2020) . In this report, we describe neurophysiological findings from a patient who developed severe muscular weakness, likely due to CIM, after hospitalization for COVID-19.

A 62-year-old woman with a history of hypertension developed fever, cough, myalgia, and diarrhea at the beginning of March 2020. After a few days of treatment with levofloxacin, which resulted in no clinical improvement, she went to the emergency room of a COVID hospital in Palermo, Italy, where SARS-CoV-2 infection was diagnosed by chest computed tomography (CT) and nasopharyngeal swab testing for SARS-CoV-2 RNA. Seven days after clinical onset, the patient was admitted to an infectious disease unit, where she was treated with lopinavir/ritonavir, hydroxychloroquine, and tocilizumab. Nine days after onset, the patient's respiratory function worsened, necessitating transfer to an ICU, where she underwent endotracheal intubation and mechanical ventilation. The ICU stay was complicated by Staphylococcus aureus and Candida tropicalis bloodstream infections. During her ICU stay, the patient received therapy with neuromuscular blocking agents, antibiotics, antifungal drugs, and corticosteroids. After 28 days, she J o u r n a l P r e -p r o o f was moved to an infectious disease unit for 4 days, but respiratory worsening necessitated another transfer to the ICU, where she stayed for 2 days. The patient was then moved to a COVID pulmonology unit. In the first days of this stay, she presented psychomotor agitation and temporospatial disorientation; a brain CT examination was normal and, after neurological and psychiatric evaluations, the patient was treated with olanzapine for about 3 weeks, which resulted in progressive improvement of her cognitive functions. Sixty-eight days post-onset, and with SARS-CoV-2 negativity on three consecutive nasopharyngeal swab tests, the patient was moved to a rehabilitation unit. At the beginning of rehabilitative treatment, the patient required a 40% fraction of inspired oxygen and presented dyspnea after mild effort. She had muscle atrophy in the lower limbs.

Segmental muscle strength evaluation showed diffuse and symmetrical muscle weakness, ranging from 3/5 to 4/5 on the Medical Research Council scale for muscle strength assessment, and greater in the lower limbs and proximal muscles. The patient was able to walk a few steps with assistance.

Deep tendon reflexes were reduced in the lower limbs. The patient's serum creatine kinase level was normal.

Eighty days post-onset, the patient underwent a thorough neurophysiological protocol, including conventional nerve conduction studies (of the ulnar, peroneal, tibial, and sural nerves), concentric needle electromyography (EMG) of the proximal and distal muscles, and direct muscle stimulation (DMS). The neurophysiological study was performed bedside using a Micromed System Plus Evolution electromyograph (Mogliano Veneto, Italy). DMS was performed in the right quadriceps and tibialis anterior muscles using two monopolar needle electrodes (Rich et al., 1997) , and the evoked compound muscle action potential (CMAP) was recorded with two monopolar needle electrodes placed about 1.5 cm distal to the midpoint of a line connecting the two stimulating electrodes. The ratio of the amplitudes of the CMAPs evoked by motor nerve stimulation and DMS was calculated. This ratio aids discrimination between neuropathic and myopathic processes during overall neurophysiological evaluation; values < 0.5 are indicative of neuropathy and those near 1 are indicative of myopathy (Rich et al., 1997; Trojaborg et al., 2001) . The normal limits were defined as J o u r n a l P r e -p r o o f means ± two standard deviations from normative data from our laboratory (standard age-matched data for the electroneurographic studies; obtained from 14 subjects for the DMS study) (Bagnato et al., 2011) .

The neurophysiological findings are summarized in Table 1 Stay in the rehabilitation unit lasted 60 days during which the patient received a rehabilitation program 3 hours a day for 6 days a week. At discharge, she did not require oxygen supplementation, had a mild weakness in lower limb proximal muscles and was able to walk without assistance.

The patient described here had myopathy, with greater involvement of the proximal muscles in the lower limbs, probably reflecting ICU-acquired weakness. Indeed, the patient met the clinical and neurophysiological criteria for CIM (Stevens et al., 2009) . The pathophysiology of CIM is complex and not fully understood, but it probably involves microcirculatory changes, metabolic alterations, electrical muscle alterations with abnormal excitation-contraction coupling, and energetic failure with mitochondrial dysfunction (Zhou et al., 2014) . A recent metanalysis identified several risk factors associated significantly with ICU-acquired weakness (including CIM and/or critical illness polyneuropathy) (Yang et al., 2018) ; among them, female sex, sepsis, hyperglycemia, use of neuromuscular blocking agents, and lengthy mechanical ventilation and ICU stay were present in this case. Preventive and supportive measures, such as glycemic control, nutritional intervention, early mobilization, and physical therapy, but no specific therapy, have been shown to be beneficial in CIM management [Zhou et al. 2014; Vanhorebeek et al., 2020] . How COVID-19 make patients susceptible J o u r n a l P r e -p r o o f to muscle damage is an open question. In the previous coronavirus outbreak, causing the severe acute respiratory syndrome in 2002-2004, a postmortem study showed a spectrum of myopathic changes, suggesting a common occurrence of CIM in non-survived patients (Leung et al., 2005) .

In conclusion, increasing evidence shows that patients with SARS-CoV-2 infection may develop various neurological complications as a direct or indirect viral action (Pinzon et al., 2020) . In addition, ICU-acquired weakness should be suspected and properly diagnosed in all patients who develop symmetrical weakness after hospitalization for COVID-19. In light of the large number of patients with COVID-19 who require lengthy ICU stays, many of these patients are very likely to develop ICU-acquired weakness, as did the patient described here, in the next months. Since rehabilitation programs can be effective to reverse muscle weakness caused by CIM, health systems must plan to provide adequate access to rehabilitative facilities for patients requiring both pulmonary and motor rehabilitative treatment after COVID-19.

This work received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Because this report just reviewed clinical data, there was no need of a specific ethical approval.

Informed consent was signed by the patient for the publication of this report.

J o u r n a l P r e -p r o o f ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

Neuromuscular involvement in vegetative and minimally conscious states following acute brain injury

Myopathic changes associated with severe acute respiratory syndrome: a postmortem case series

Incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease 2019 in California and Washington: prospective cohort study

Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis

Direct muscle stimulation in acute quadriplegic myopathy

A framework for diagnosing and classifying intensive care unit-acquired weakness

Electrophysiologic studies in critical illness associated weakness: myopathy or neuropathy -a reappraisal

Van den Berghe G. ICU-acquired weakness

Risk factors for intensive care unit-acquired weakness: A systematic review and meta-analysis

Critical illness polyneuropathy and myopathy: a systematic review



